The S-(+) isomer of the (2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester of formula I
known under the non-proprietary name clopidogrel (or S-clopidogrel), is an effective antithrombic agent, indicated especially for prevention of artherosclerotic events in patients having experienced infarction or stroke or suffering from ischemic disease of lower limbs. It is, therefore, crucial for preventing recurrence of such diseases and, thus, prevents fatal consequences of these diseases.
Process of preparation of clopidogrel (substance of formula I) is described in a number of patents. Those that make up the most relevant part of the prior art with respect to the present invention are cited herein.
In patent EP 99802, a group of substances was described with the antiaggregation effect, which includes also the substance of formula I. In the patent, optically active isomers of these substances are also mentioned. Preparation of substances of the type of clopidogrel (I) was, according to the patent, carried out via reaction of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine with an alpha-chloro derivative of an alpha-(chlorophenyl)-acetic acid ester in the presence of a base.
Further development published in patent EP 281459 showed that of the substances described in the above mentioned patent hydrogensulfate (the HSO4− anion) of substance of formula I is the most advantageous one. This salt was tested for antiaggregation effects and compared with some other salts.
In EP 281459, a method of preparation of this salt is also described, which consists in resolution of the racemic mixture of the substance of formula I with the R isomer of formula II

The mixture of substances I and II was transferred to salts of R(−) camphorsulfonic acid in acetone and subsequently crystallized. This was followed with several recrystallizations also from acetone, until sufficiently pure camphorsulfonate of substance I was obtained.
In patent U.S. Pat. No. 6,737,411, an improved method of said resolution is described. It consists in preparation of camphorsulfonic acid in a mixture of C1 up to C12 hydrocarbons with a suitable co-solvent, which is selected from the group including dimethylformamide, butanol or acetone. In a preferable embodiment camphorsulfonic acid is dissolved in dimethylformamide and added to a solution of a mixture of substances I and II in toluene.
Racemization of the undesired enantiomer R, consisting in converting a portion thereof to the S enantiomer and recycling this mixture to the resolving reaction, is described in patent application WO 02/059128, where an inorganic base is used for racemization in the ratio 1:1. While this procedure reliably yields a racemic mixture of the S(+) and R(−) enantiomers, saponification of esters I and II takes place. In order to allow for return of the racemic mixture back to the resolving reaction, it is necessary to convert the alkali salts back to esters. This requires further steps that increase losses and tediousness of the production.
Said drawback has been eliminated by patent U.S. Pat. No. 6,737,411, according to which a catalytic amount of an alcoholate, preferably potassium tert-butanolate, is used. The method leads to a racemic mixture of esters but the reaction can take place only in an absolutely anhydrous environment. That is why the reaction mixture has to be first dried and its water content controlled, which has to be lower than 0.05% (according to KF).
However, we have found a method that leads to a racemic mixture of esters, but that does not require strictly anhydrous environment.